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Jing Sun, Yarong Mu, Yuanyuan Jiang, Ruilong Song, Jianxin Yi, Jingsong Zhou, Jun Sun, Xinan Jiao, Richard A Prinz, Yi Li, Xiulong Xu
Autophagy plays a central role in degrading misfolded proteins such as mutated superoxide dismutase 1 (SOD1), which forms aggregates in motor neurons and is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is activated when UNC-51-like kinase 1 (ULK1) is phosphorylated at S555 and activated by AMP-activated protein kinase (AMPK). Autophagy is suppressed when ULK1 is phosphorylated at S757 by the mechanistic target of rapamycin (mTOR). Whether p70 S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, can also regulate autophagy remains uncertain...
March 14, 2018: Cell Death & Disease
Qiaojie Chen, Shaokun Wu, Yaojun Wu, Liang Chen, Qingjiang Pang
BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease that with the complication of disability, while inflammation is the important response of OA. MiR-149 was down-regulated in the OA tissues, while the potential mechanism of miR-149 in OA is unclear. METHODS: A total of 20 OA patients and 20 healthy persons were enrolled in the present study. Real-time PCR was used to detect miR-149 and the mRNA expression of TAK1, western blot was used to detect the protein expression of TAK1...
March 7, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Jaya Talreja, Lobelia Samavati
Post viral infection bacterial pneumonia is a major cause of morbidity and mortality associated with both seasonal and pandemic influenza virus illness. Despite much efforts put into the discovery of mechanisms of post viral-bacterial infections and their complications in recent years, the molecular mechanisms underlying the increased susceptibility to bacterial infection remain poorly understood. In this study, we focused on the pathways regulating immune responses in murine macrophages and modeled post viral-bacterial infections through pretreatment of bone marrow-derived macrophages (BMDMs) with a toll-like receptor (TLR) 7/8 ligand (R848) and subsequent challenge with TLR2/4 agonists to mimic bacterial infection...
2018: Frontiers in Immunology
Fernando Gallardo, Joan Bertran, Erika López-Arribillaga, Jéssica González, Silvia Menéndez, Ignacio Sánchez, Luis Colomo, Mar Iglesias, Marta Garrido, Luis Francisco Santamaría-Babí, Ferran Torres, Ramon M Pujol, Anna Bigas, Lluís Espinosa
Cutaneous T-cell lymphomas (CTCLs) represent different subtypes of lymphoproliferative disorders with no curative therapies for the advanced forms of the disease (namely mycosis fungoides and the leukemic variant, Sézary syndrome). Molecular events leading to CTCL progression are heterogeneous, however recent DNA and RNA sequencing studies highlighted the importance of NF-κB and β-catenin pathways. We here show that the kinase TAK1, known as essential in B-cell lymphoma, is constitutively activated in CTCL cells, but tempered by the MYPT1/PP1 phosphatase complex...
February 22, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Mingo Ming-Ho Yung, Hermit Wai-Man Tang, Patty Chun-Hui Cai, Thomas Ho-Yin Leung, Siew-Fei Ngu, Karen Kar-Loen Chan, Dakang Xu, Huijuan Yang, Hextan Yuen-Sheung Ngan, David Wai Chan
Intraperitoneal metastasis is a common occurrence and is usually involved in the poor prognosis of ovarian cancer. Its specific metastatic pattern implies that certain indispensable microenvironmental factors secreted in the peritoneal cavity can direct metastatic ovarian cancer cells to permissive niches for secondary lesion formation. However, the underlying molecular mechanisms are ill defined. Herein, we report that GRO-α and IL-8 are predominately upregulated in culture media derived from either normal or cancerous omenta and are associated with increased ovarian cancer aggressiveness...
2018: Theranostics
Matthew Stephen Mangan, Eicke Latz
In this issue of JEM, Malireddi et al. ( demonstrate that macrophage-specific loss of TAK1 causes spontaneous NLRP3 inflammasome activation, driven by unregulated TNF secretion and signaling. This has implications for therapeutically targeting TAK1, enhancing its potential function as an anticancer drug treatment.
March 5, 2018: Journal of Experimental Medicine
Jun Zhou, Youling Fan, Jiying Zhong, Zhenxing Huang, Teng Huang, Sen Lin, Hongtao Chen
The ability of cisplatin (cis-diamminedichloroplatinum II) toxicity to induce acute kidney injury (AKI) has attracted people's attention and concern for a long time, but its molecular mechanisms are still widely unknown. We found that the expression of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) could be increased in kidneys of mice administrated with cisplatin. Autophagy is an evolutionarily conserved catabolic pathway and is involved in various acute and chronic injuries. Moreover, p38 MAPK (mitogen-activated protein kinase) and ERK regulate autophagy in response to various stimuli...
March 5, 2018: Journal of Cellular and Molecular Medicine
R K Subbarao Malireddi, Prajwal Gurung, Jayadev Mavuluri, Tejasvi Krishna Dasari, Jeffery M Klco, Hongbo Chi, Thirumala-Devi Kanneganti
The NOD-like receptor (NLR)-P3 inflammasome is a global sensor of infection and stress. Elevated NLRP3 activation levels are associated with human diseases, but the mechanisms controlling NLRP3 inflammasome activation are largely unknown. Here, we show that TGF-β activated kinase-1 (TAK1) is a central regulator of NLRP3 inflammasome activation and spontaneous cell death. Absence of TAK1 in macrophages induced spontaneous activation of the NLRP3 inflammasome without requiring toll-like receptor (TLR) priming and subsequent activating signals, suggesting a distinctive role for TAK1 in maintaining NLRP3 inflammasome homeostasis...
March 2, 2018: Journal of Experimental Medicine
Hadjer Saidi, Julie Bérubé, Fatima Laraba-Djebari, Djelila Hammoudi-Triki
Androctonus australis hector (Aah) scorpion venom is well known to induce a systemic inflammatory response associated with cell infiltration in lung and edema formation. The present study investigate (i) in vivo the evolution of lung and systemic inflammation triggered by Aah venom and (ii) analyze in vitro the signaling cascade, upstream of inflammatory cytokine expression after Aah venom-stimulated mouse alveolar macrophage (MH-S), the main resident immune cells in the lung. The inflammation induced by Aah venom was assessed in mice through inflammatory cell count, nitric oxide metabolite, and lactate dehydrogenase (LDH) activity in blood, concordantly with neutrophil sequestration in tissue and lung histology...
February 28, 2018: Inflammation
Donghu Zhou, Qianqian Shao, Xu Fan, Peng Wu, Weiran Lin, Handong Wei, Fuchu He, Ying Jiang
Alternative splicing (AS) generates multiple isoforms from a single precursor mRNA, and these isoforms usually exhibit different tissue distributions and functions. Aberrant protein isoforms can lead to abnormalities in protein function and may even result in genetic disorders or cancer. In recent years, splice-switching oligonucleotides (SSOs) have emerged as a promising therapeutic strategy for several neurological diseases, but the efficacy of this strategy in other organs is less reported. In this study, we designed and synthesized SSOs targeting the splicing regulators of exon 12 of the Tak1 gene, inducing variant switching between Tak1-A and Tak1-B...
February 20, 2018: Biochemical and Biophysical Research Communications
Silvia Morlino, Marco Castori, Chiara Dordoni, Valeria Cinquina, Graziano Santoro, Paola Grammatico, Marina Venturini, Marina Colombi, Marco Ritelli
Heterozygous variants in MAP3K7, encoding the transforming growth factor-β-activated kinase 1 (TAK1), are associated with the ultrarare cardiospondylocarpofacial syndrome (CSCFS). Specific gain-of-function variants in the same gene cause the allelic frontometaphyseal dysplasia type 2. Phenotypic series of frontometaphyseal dysplasia also comprise variants in FLNA (type 1) and two patients with a heterozygous variant in TAB2 (type 3). We report on a 7-year-old girl with CSCFS due to the novel heterozygous c...
February 21, 2018: European Journal of Human Genetics: EJHG
Qing-Qing Fang, Xiao-Feng Wang, Wan-Yi Zhao, Shi-Li Ding, Bang-Hui Shi, Ying Xia, Hu Yang, Li-Hong Wu, Cai-Yun Li, Wei-Qiang Tan
Angiotensin-converting enzyme inhibitors (ACEIs) can improve the fibrotic processes in many internal organs. Recent studies have shown a relationship between ACEI with cutaneous scar formation, although it has not been confirmed, and the underlying mechanism is unclear. In this study, we cultured mouse NIH 3T3 fibroblasts with different concentrations of ACEI. We measured cell proliferation with a Cell Counting Kit-8 and collagen expression with a Sirius Red Collagen Detection Kit. Flow cytometry and western blotting were used to detect transforming growth factor β1 (TGF-β1) signaling...
February 20, 2018: Scientific Reports
Woo Seok Yang, Eunju Yang, Min-Jeong Kim, Deok Jeong, Deok Hyo Yoon, Gi-Ho Sung, Seungihm Lee, Byong Chul Yoo, Seung-Gu Yeo, Jae Youl Cho
Momordica charantia known as bitter melon is a representative medicinal plant reported to exhibit numerous pharmacological activities such as antibacterial, antidiabetic, anti-inflammatory, anti-oxidant, antitumor, and hypoglycemic actions. Although this plant has high ethnopharmacological value for treating inflammatory diseases, the molecular mechanisms by which it inhibits the inflammatory response are not fully understood. In this study, we aim to identify the anti-inflammatory mechanism of this plant. To this end, we studied the effects of its methanol extract (Mc-ME) on lipopolysaccharide (LPS)-stimulated RAW264...
February 20, 2018: American Journal of Chinese Medicine
Fredrik Ghosh, Hodan Abdshill, Karin Arnér, Ulrikke Voss, Linnéa Taylor
The purpose of this study was to explore retina-intrinsic neuroinflammatory reactions, effects on neuronal survival, relationship with classic gliosis, and possible role of the toll-like receptor 4 (TLR4). To isolate the adult retina from the systemic immune system, a previously described large animal explant culture model was used in which full-thickness porcine retinal sheets can be kept in vitro for extended time periods. Explants were kept for 5 days in vitro (DIV) and were treated with either; lipopolysaccharide (LPS), a Toll-like receptor-4 (TLR4) inhibitor (CLI-095), LPS + CLI-095, or solvent vehicle throughout the culture period after which retinal sections were examined with hematoxylin and eosin staining and extensive immunohistochemistry...
February 7, 2018: Experimental Eye Research
Sinead E Shortall, Ola H Negm, Maxine Fowler, Lucy C Fairclough, Patrick J Tighe, Peter M Wigmore, Madeleine V King
Post-weaning social isolation of rats produces neuroanatomical, neurochemical and behavioral alterations resembling some core features of schizophrenia. This study examined the ability of the 5-HT6 receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister hooded rats (weaned on post-natal days 21-24 and housed individually or in groups of 3-4) received six i...
February 8, 2018: Molecular Neurobiology
Sajedah M Hindi, Shuichi Sato, Guangyan Xiong, Kyle R Bohnert, Andrew A Gibb, Yann S Gallot, Joseph D McMillan, Bradford G Hill, Shizuka Uchida, Ashok Kumar
Skeletal muscle mass is regulated by a complex array of signaling pathways. TGF-β-activated kinase 1 (TAK1) is an important signaling protein, which regulates context-dependent activation of multiple intracellular pathways. However, the role of TAK1 in the regulation of skeletal muscle mass remains unknown. Here, we report that inducible inactivation of TAK1 causes severe muscle wasting, leading to kyphosis, in both young and adult mice.. Inactivation of TAK1 inhibits protein synthesis and induces proteolysis, potentially through upregulating the activity of the ubiquitin-proteasome system and autophagy...
February 8, 2018: JCI Insight
Chih-Sung Hsieh, Jiin-Haur Chuang, Ming-Huei Chou, Ying-Hsien Kao
The role of transforming growth factor-β activated kinase 1 (TAK1) in modulating the function of Kupffer cells (KCs) within cholestatic livers remains unclear. This study examined the immunopharmacological action of dexamethasone (DEX) in modulating hepatic TAK1 expression and related signaling activity in a rat model of bile duct ligation-mimicked obstructive jaundice. The in vitro effects of DEX on porcine biliary extract (PBE)-modulated gene expression and phagocytosis of KCs were examined using a rat alveolar macrophage cell line (NR8383 cells)...
February 4, 2018: International Immunopharmacology
Jennifer L Graef, Elizabeth Rendina-Ruedy, Erica K Crockett, Ping Ouyang, Jarrod B King, Robert H Cichewicz, Edralin A Lucas, Brenda J Smith
Dried plum supplementation has been shown to enhance bone formation while suppressing bone resorption. Evidence from previous studies has demonstrated that these responses can be attributed in part to the fruit's polyphenolic compounds. The purpose of this study was to identify the most bioactive polyphenolic fractions of dried plum with a focus on their osteogenic activity and to investigate their mechanisms of action under normal and inflammatory conditions. Utilizing chromatographic techniques, six fractions of polyphenolic compounds were prepared from a crude extract of dried plum...
September 29, 2017: Journal of Nutritional Biochemistry
Xia Liu, Satoru Hayano, Haichun Pan, Maiko Inagaki, Jun Ninomiya-Tsuji, Hongchen Sun, Yuji Mishina
BMP signaling plays a critical role in craniofacial development. Augmentation of BMPR1A signaling through neural crest-specific expression of constitutively active Bmpr1a (caBmpr1a) results in craniofacial deformities in mice. To investigate whether deletion of Tak1 may rescue the craniofacial deformities caused by enhanced Smad-dependent signaling through caBMPR1A, we generated embryos to activate transcription of caBmpr1a transgene and ablate Tak1 in neural crest derivatives at the same time. We found that deformities of the double mutant mice showed more severe than those with each single mutation, including median facial cleft and cleft palate...
February 7, 2018: Genesis: the Journal of Genetics and Development
Tanmoy Mondal, Indira Bag, Pushpavalli Sncvl, Koteswara Rao Garikapati, Utpal Bhadra, Manika Pal Bhadra
Argonaute family proteins are well conserved among all organisms. Its role in mitotic cell cycle progression and apoptotic cell elimination is poorly understood. Earlier we have established the contribution of Ago-1 in cell cycle control related to G2/M cyclin in Drosophila. Here we have extended our study in understanding the relationship of Ago-1 in regulating apoptosis during Drosophila development. Apoptosis play a critical role in controlling organ shape and size during development of multi cellular organism...
2018: PloS One
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